Cerebellum最新文献

The recognition that there is an innate immune system of the brain, referred to as the neuroimmune system, that preforms many functions comparable to that of the peripheral immune system is a relatively new concept and much is yet to be learned. The main cellular components of the neuroimmune system are the glial cells of the brain, primarily microglia and astrocytes. These cell types preform many functions through secretion of signaling factors initially known as immune factors but referred to as neuroimmune factors when produced by cells of the brain. The immune functions of glial cells play critical roles in the healthy brain to maintain homeostasis that is essential for normal brain function, to establish cytoarchitecture of the brain during development, and, in pathological conditions, to minimize the detrimental effects of disease and injury and promote repair of brain structure and function. However, dysregulation of this system can occur resulting in actions that exacerbate or perpetuate the detrimental effects of disease or injury. The neuroimmune system extends throughout all brain regions, but attention to the cerebellar system has lagged that of other brain regions and information is limited on this topic. This article is meant to provide a brief introduction to the cellular and molecular components of the brain immune system, its functions, and what is known about its role in the cerebellum. The majority of this information comes from studies of animal models and pathological conditions, where upregulation of the system facilitates investigation of its actions.

In the past few years, SARS-CoV-2 infection has substantially impacted public health. Alongside respiratory symptoms, some individuals have reported new neurological manifestations or a worsening of pre-existing neurological conditions. We previously documented two cases of essential tremor (ET) who experienced a deterioration in tremor following SARS-CoV-2 infection. However, the effects of SARS-CoV-2 on ET remain largely unexplored. This study aims to evaluate the impact of SARS-CoV-2 infection on a relatively broad sample of ET patients by retrospectively comparing their clinical and kinematic data collected before and after the exposure to SARS-CoV-2. We surveyed to evaluate the impact of SARS-CoV-2 infection on tremor features in ET. Subsequently, we retrospectively analysed clinical and kinematic data, including accelerometric recordings of postural and kinetic tremor. We included 36 ET patients (14 females with a mean age of 71.1 ± 10.6 years). Among the 25 patients who reported SARS-CoV-2 infection, 11 (44%) noted a subjective worsening of tremor. All patients reporting subjective tremor worsening also exhibited symptoms of long COVID, whereas the prevalence of these symptoms was lower (50%) in those without subjective exacerbation. The retrospective analysis of clinical data revealed a tremor deterioration in infected patients, which was not observed in non-infected patients. Finally, kinematic analysis revealed substantial stability of tremor features in both groups. The study highlighted a potential correlation between the SARS-CoV-2 infection and clinical worsening of ET. Long COVID contributes to a greater impact of tremor on the daily life of ET patients.

Post-traumatic stress disorder (PTSD) is a debilitating mental health condition characterized by recurrent re-experiencing of traumatic events. Despite increasing evidence suggesting that the cerebellum is involved in PTSD pathophysiology, it remains unclear whether this involvement is related to symptoms directly resulting from previous trauma exposure, such as involuntary re-experiencing of the traumatic events, or reflects a broader cerebellar engagement in negative affective states. In this study, we investigated the specific role of the cerebellum in PTSD by employing a script reactivation paradigm with personalized traumatic and sad autobiographical memories in 28 individuals diagnosed with chronic PTSD. Functional magnetic resonance imaging (fMRI) data were collected while participants listened to their own autobiographical narratives recounted by a third person. Activation in the right cerebellar lobule VI was uniquely associated with traumatic autobiographical recall and was parametrically modulated by the severity of re-experiencing symptoms. In contrast, cerebellar Crus II showed increased activation during both traumatic and sad autobiographical recall, suggesting a broader involvement in processing negative emotions. Our findings highlight the unique contribution of the right cerebellar lobule VI in the processing of traumatic autobiographical memories, potentially through its engagement in low-level representation of sensory and emotional aspects of traumatic events.

COVID-19-associated cerebellar ataxia has rarely been reported and its clinical characteristics remain understudied. This study aims to report patients with COVID-19-associated cerebellar ataxia from our institution. COVID-19-associated cerebellar ataxia was diagnosed based on the prodromal COVID-19 infection and the exclusion of other causes. This study provides a summary of the patients' clinical presentations, neuroimaging features, and the results of anti-cerebellar antibody examinations. Our study included 11 patients and 4 were male. The median onset age was 38 years. Five patients also demonstrated signs of encephalopathy. Brain magnetic resonance imaging (MRI) was either unremarkable (n = 6) or showed bilateral cerebellar lesions (n = 5), which were typically transient, although brain atrophy could be observed later in the disease course. Anti-Homer-3 and anti-Yo antibodies were each detected in one patient, respectively. All patients received immunotherapy and nine improved. Compared with the late-onset group, individuals who exhibited ataxia earlier following COVID-19 onset (interval<5 days) were significantly younger [median age 18 (15.5-31) vs. 53.5 (44-64.8) years, p = 0.009] and more likely to present with encephalopathy (5/5 vs. 0/6, p = 0.002).They also experienced more severe symptoms [median modified Rankin scale (mRS) score at zenith 5 (5-5) vs. 2 (1.75-2.75), p = 0.017] and had a less favorable prognosis [median mRS score at the last follow-up 4 (2-5) vs. 1 (0-1.25), p = 0.009]. COVID-19-associated cerebellar ataxia can appear with encephalopathy. Brain MRI may show transient bilateral cerebellar lesions and brain atrophy later. Patients who exhibited ataxia earlier following COVID-19 were younger, had more severe symptoms and poorer outcomes.

Bi-allelic pathogenic variants in GRID2 have been initially associated to an autosomal recessive form of spinocerebellar ataxia, namely SCAR18. Subsequently, few monoallelic cases have been described. Here we present a new subject harboring a novel de novo heterozygous GRID2 missense variant presenting with progressive ataxia together with cerebellar atrophy and, for the first time, alpha-fetoprotein (AFP) elevation. We retrospectively collected data of the patient followed at our clinic. Genetic analysis was performed through clinical exome sequencing with an in-house in-silico ataxia-related genes panel. Variant effect prediction was performed through in silico modeling. The patient had normal psychomotor development except for mild fine and gross motor impairment. In adolescence, he started presenting dysarthria and progressive ataxia. Blood tests showed significant AFP elevation. Brain MRI showed cerebellar atrophy mainly involving the vermis. The novel de novo heterozygous GRID2 (c.1954C>A; p.Leu652Ile) missense variant was disclosed. This variant is located within a highly conserved site with low tolerance to variation and it is predicted to cause protein structure destabilization. GRID2 expression appears to be influenced by other genes related with ataxia and AFP elevation, like ATM and APTX, suggesting a possible shared mechanism. This additional patient increases the scarce literature and genotypic spectrum of the GRID2-related ataxia and evidences a fairly homogeneous phenotype of ataxia with oculomotor abnormalities for the autosomal-dominant form. Alfa-fetoprotein elevation is a novel finding in this condition and this data must be confirmed in larger case-series to definitively state that GRID2-related ataxia can be included among ataxias with AFP increase.

Background: The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease.

Methods: a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05).

Results: 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5 mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516).

Discussion: Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.

Polyglutamine spinocerebellar ataxias (polyQ SCAs) represent the most prevalent subtype of SCAs. The primary pathogenic mechanism is believed to be the gain-of-function neurotoxicity of polyQ proteins. Strategies such as enhancing the degradation or inhibiting the accumulation of these mutant proteins are pivotal for reducing their toxicity and slowing disease progression. The protein quality control (PQC) system, comprising primarily molecular chaperones and the ubiquitin‒proteasome system (UPS), is essential for maintaining protein homeostasis by regulating protein folding, trafficking, and degradation. Notably, polyQ proteins can disrupt the PQC system by sequestering its critical components and impairing its proteasomal functions. Therefore, restoring the PQC system through genetic or pharmacological interventions could potentially offer beneficial effects and alleviate the symptoms of the disease. Here, we will provide a review on the distribution, expression, and genetic or pharmacological intervention of protein quality control system in cellular or animal models of PolyQ SCAs.

Background: Gillespie syndrome is a rare disorder caused by pathogenic variants in ITPR1 gene and characterized by the typical association of cerebellar ataxia, bilateral aniridia and intellectual disability. Since its first description in 1965, less than 100 patients have been reported and only 30 with a molecular confirmation.

Methods: We present two additional cases, both carrying a loss-of-function variant in the Gly2539 amino acid residue. We describe the clinical evolution of the patients, one of whom is now 17 years old, and discuss the updated phenotypic spectrum of the disorder.

Results: The study gives an overview on the condition, allowing to confirm important data, such as an overall positive evolution of development (with some patient not presenting intellectual disability), a clinical stability of the neurological signs (regardless of a possible progression of cerebellar atrophy) and ocular aspects, and a low prevalence of general health comorbidities.

Discussion: Data about development and the observation of middle-aged patients lend support to the view that Gillespie is to be considered a non-progressive cerebellar ataxia, making this concept a key point for both clinicians and therapists, and for the families.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, and the association with immune-related adverse events (irAEs) is well-established. However, cerebellar irAEs are poorly defined and their relationship with paraneoplastic disorders remains unclear. Our aim was (i) to characterize cerebellar irAE; (ii) to compare it with paraneoplastic cerebellar ataxia (PCA). We performed a multicenter, retrospective, cohort study of patients developing new-onset, immune-mediated, isolated/predominant cerebellar dysfunction after ICI administration. In addition, a systematic review following PRISMA guidelines was performed. Cerebellar irAE cases were compared with a consecutive cohort of patients with PCA. Overall, 35 patients were included, of whom 12 were original cases (males: 25/35 (71%), median age: 65 [range: 20-82]). The most frequent tumor was non-small cell lung cancer (12/35, 34%). Anti-PD1 were adopted in 19/35 (54%). Symptoms developed at a median of 11 weeks after ICI onset. Neuronal antibodies were detected in 15/31 patients tested (48%). Cerebrospinal fluid was inflammatory in 25/30 (83%). Magnetic resonance imaging showed cerebellar hyperintensities in 8/35 (23%). Immunotherapy was applied in 33/35 cases (94%), and most patients improved with residual disability (16/35, 46%). When compared with a series of PCA (n = 15), the cerebellar irAE group was significantly more associated with male sex, lung cancer (rather than gynecological/breast cancers), isolated ataxia, and a better outcome. We provide a detailed characterization of cerebellar irAE. Compared to PCA, differences exist in terms of tumor association, clinical features, and outcome. Clinical presentation-antibody-tumor triad in the ICI group only partially reflects the associations described in paraneoplastic disorders.

Multiple system atrophy-cerebellar type (MSA-C) exhibits faster disease progression than does hereditary spinocerebellar degeneration (hSCD). In this study, we aimed to investigate the differences in the treatment effects and sustainability of intensive rehabilitation between patients with hSCD and those with MSA-C. Forty-nine patients (hSCD = 30, MSA-C = 19) underwent a 2- or 4-week intensive rehabilitation program. Balance function was evaluated using the scale for the assessment and rating of ataxia (SARA) and the balance evaluation systems test (BESTest) at pre-intervention, post-intervention, and 6-month follow-up. Notably, both groups demonstrated beneficial effects from the rehabilitation intervention. However, differences were observed in the magnitude and duration of these effects. In the hSCD group, the SARA scores at follow-up remained similar to those at baseline, indicating sustained benefits. However, the MSA-C group showed some deterioration in SARA scores compared with baseline scores but maintained improvements on the BESTest, demonstrating partial sustainability. Differences, mainly in sustainability, were observed between the hSCD and MSA-C groups. This may be due to varying rates of symptom progression. The findings of this study are significant when considering the frequency of follow-ups based on disease type.